PROJECT ABSTRACT To date, colorectal cancer (CRC) is the third most commonly diagnosed cancer and cause of cancer death in the US. Although the median survival of patients with metastatic CRC has improved to 2 years over the last three decades, chance for cure remains less than 10%. These unfortunate facts translate into increasing number of patients being actively treated with chemotherapy, which poses huge financial burden on the patients, their families and the health system. Therefore, effective systemic therapy with curative potential is clearly an unmet medical need for these patients. Current standard treatments consist of strong chemotherapy that is highly toxic but with only 50% chance of working. For those who initially benefit from chemotherapy, disease progression as a result of drug resistance is inevitable. We now found, for the first time in literature, that CRC cells frequently armor themselves by activating the innate immune signaling, a self-defense mechanism that is usually summoned when cells are injured or invaded by microorganisms. In doing so CRC cells become highly invasive and resistant to chemotherapeutics. Our approach is to ?deactivate? such defense mechanism in CRC cells by inhibiting Interleukin-1 Receptor-Associated Kinase 4 (IRAK4), the master switch that controls the innate immune pathway. By doing so we found that CRC cells become greatly weakened and are much more vulnerable to chemotherapy. We plan to further confirm and study these potentially impactful findings by pursuing the following two aims: 1. Aim 1: We will utilize CRC cell lines and patient-derived xenografts to clearly investigate the role of IRAK4 in various aspects of CRC biology including the ability to grow in 3-dimensional culture, invasion, resistance to chemotherapy and metastasis. These studies will clearly establish if IRAK4 is a novel therapeutic target in CRC that should be pursued in the clinic. 2. Aim 2: CRC is a cancer that is closely associated with chronic inflammation, in which IRAK4 may play a key role. In this aim we will study, using human CRC samples and a genetic CRC mouse model, whether IRAK4 is progressively activated following tumor progression, and if so, whether activated IRAK4 in CRC is associated with poor prognosis, as we have reported to be the case in pancreatic cancer. We will further characterize whether loss of IRAK4 will thwart CRC initial or progression in this genetic mouse model. These studies will provide new scientific knowledge and the potential value of IRAK4 inhibition in chemoprevention. Page 1 of 1